The selective aryl hydrocarbon receptor modulator 6-methyl-1,3,8-trichlorodibenzofuran inhibits prostate tumor metastasis in TRAMP mice

Abstract

The aryl hydrocarbon receptor (AhR) is a basic-helix-loop-helix transcription factor that binds halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr −/− ) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate tumors with much greater frequency than AhR wild-type (Ahr +/+ ) TRAMP mice, suggesting that the AhR has tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM), 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate tumorigenesis. TRAMP mice on the standard C57BL/6J × FVB genetic background were fed 0, 10, or 40 mg 6-MCDF/kg diet beginning at 8 weeks of age. Tumor incidence, pelvic lymph node metastasis, and serum vascular endothelial growth factor (VEGF) concentrations were determined at 140 days of age. Prostate tumor incidence and size were not significantly reduced in mice fed 6-MCDF. However, the frequency of pelvic lymph node metastasis was reduced 5-fold in mice fed the 40 mg 6-MCDF/kg diet. Serum VEGF concentrations were also reduced by 6-MCDF treatment, particularly in mice without prostate tumors, and 6-MCDF was shown to act directly on cultured prostates to inhibit VEGF secretion. Together, these results suggest that 6-MCDF inhibits metastasis, in part, by inhibiting prostatic VEGF production prior to tumor formation. This is the first report that 6-MCDF can confer protection against prostate cancer in vivo.

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…For instance, 12 weeks of feeding 6-methyl-1,3,8-trichlorodibenzofuran inhibited metastasis in a mouse model of prostate tumorigenesis, in part by inhibiting prostatic vascular endothelial growth factor production prior to tumor formation (Fritz et al, 2009). SAhRMs aim to modify AhR activation in such a way that the beneficial effects outweigh toxic effects (e.g., those known from dioxins).…”

2,3,7,8-Tetrachlorodibenzo- p -dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice

“…Yet when all mice in these treatment groups are considered the complete protection against metastasis by TCDD was very close to being statistically significant ( p = 0.06). These observations, particularly in light of our previous finding that 6-methyl-1,3,8-trichlorodibenzofuran significantly inhibited NEPC metastasis in TRAMP mice (Fritz et al, 2009), suggest that AHR signaling pathway activation may protect against prostate tumor metastasis. Additional research would be needed to determine how long the apparent protection against visibly obvious pelvic lymph node metastasis persists, and whether metastasis to other sites is also inhibited.…”

“…We then observed that a selective AHR modulator (SAHRM), 6-methyl-1,3,8-trichlorodibenzofuran, inhibited prostate tumor metastasis in TRAMP mice (Fritz et al, 2009). The fact that IUL TCDD exposure increased the incidence of prostatic cribriform structures in wild-type mice (Fritz et al, 2005) raised the possibility that such exposure might increase prostate cancer incidence in animals capable of developing this disease.…”

Inhibitory effect of the low‑toxic exogenous aryl hydrocarbon receptor modulator 3'3‑diindolylmethane on gastric cancer in mice

“…Differences in lifestyle, environment and diet may also have a role in the high incidence and mortality associated with GCa (3). The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in cell differentiation and carcinogenesis, including in lung cancer (4), breast cancer (5) and prostate cancer (6). There are currently few studies involving the AhR pathway and GCa (7).…”